The invention relates to solid agents, comprising polymorphic lipid particles, with UV radiation-absorbing and/or reflecting action for application on the skin, mucous membranes, scalp and hair for protection against health-damaging UV radiation and for strengthening the natural skin barrier.
With the increase in the ozone hole and the worldwide decrease in the thickness of, the ozone layer and the resultant increasing exposure of the human skin to health-damaging UV radiation, there is an increasing need and necessity for agents which protect the skin from UV radiation, that is, which weaken or, ideally, completely block the UV radiation. The health-damaging effect of UV rays makes itself apparent in the form of skin cancer (e.g. melanoma), among other things. The increase in UV radiation load on the skin in recent years has led to a great increase in skin cancers. Whereas the incidence of some cancer types is declining, melanoma of the skin is one of the cancer types with the highest rate of increase, as a result of the increasing UV load. New cases of malignant melanoma are doubling every 5 years (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843). The population of countries with high and intensive exposure to the sun is affected in particular, e.g. ozone hole above South Chile, New Zealand and Australia. Thus, the incidence of malignant melanoma in Australia is five times higher than in Central Europe (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843).
The traditional approach to providing protection from UV radiation is the incorporation of molecules which absorb UV radiation (so-called UV blockers) in creams or lotions which are applied to the skin as protection against the sun and remain there for hours. (N. J. Lowe, Photoprotection, Seminars in Dermatology, Vol. 9, NO. 1, 1990, 78-83). Strictly speaking, the term xe2x80x9cUV blockerxe2x80x9d is misleading, as the UV radiation is not completely blocked, but only lessened to a greater or lesser extent, depending on the concentration and chemical nature of the substances which are used.
One of the disadvantages of the molecular UV blockers is that, analogously to drugs incorporated into cream, they diffuse into the skin. This is desired with drugs but not with UV blockers, as they cause unwelcome side-effects.
Side-effects of UV blockers are e.g. photosensitization such as photoallergy and phototoxicity, and skin irritations. With sensitive persons, a foreign substancexe2x80x94often a topical chemical UV filterxe2x80x94is activated by UV radiation and this activated form then causes this reaction (E. Wolf, Angst vor der Sonne Pharmazeutische Zeitung 144, 1839-1843). With some substance classes (salicylides), skin irritations are so marked that they cannot be applied to the skin. This has resulted in the requirement to minimize penetration into the skin (E. Mariani, C. Neuhoff, A. Bargagna, F. Bonina, M. Giacchi, G. De Guidi, A. Velardita, Synthesis, in vitro percutaneous absorption and phototoxicity of new benzylidene derivatives of 1,3,3-trimethyl-2-oxabicyclo (2,2,2) octan-6-6-one as potential UV sunscreens, Int. J. Pharm. 161, 65-73). With good solubility in the vehicle (e.g. molecular UV blockers in the oil phase of a lotion or cream), a penetration into the skin can however come about very easily. (U. Hagedorn-Leweke, B. C. Lippold, Accumulation of sunscreens and other compounds in keratinous substrates, Eur. J. Pharm. Biopharm. 46, 215-221). The skin penetration of molecular UV blockers is thus an unsolved problem. Hence the stronger call to employ physically acting light filters which do not penetrate the skin (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843).
A further problem is that toxicological testing of UV blockers is in accordance with the guidelines for cosmetics, which are less strict than those for drug tests. UV blockers can decompose under the action of UV radiation. Reactive decomposition substances thus form which can be toxicologically problematical, especially where there is skin penetration. It is known of some UV blockers that they specifically bond to keratin structures of the skin and can therefore be washed off only with difficulty (U. Hagedorn-Leweke, B. C. Lippold, Accumulation of sunscreens and other compounds in keratinous substrates, Eur. J. Pharm. Biopharm. 46, 215-221). To minimize toxicity, an ideal sunscreen should be removable by washing after sunbathing.
The penetrationxe2x80x94and therefore the side effectsxe2x80x94can be particularly marked if the UV blockers are dissolved in the aqueous phase of oil-in-water (O/W) creams or lotions. The phase in direct contact with the skin (water phase) has a high concentration of UV blockers so that the water phase-to-skin concentration gradient is high, which, according to Fick""s first law of diffusion, promotes penetration into the skin. This is an effect which is selectively exploited in pharmacy with transdermal therapeutic patches, but which is undesirable, and must be minimized, with UV blockers.
One approach to minimizing skin penetration is the use of lipophilic UV blockers with low water-solubility. These are dissolved in the oil phase of the cream or lotion. The water phase contains a much lower concentration of UV blockers. With a favourable chemical structure of the UV blocker, this can slow down penetration into the skin as a result of the concentration gradient now being smaller, but does not avoid it. UV blocker diffused out of the wtaer phase into the skin is replaced by the diffusion of further UV blocker out of the oil phase into the water phase. The redistribution into the water phase takes place according to the Nernst""s distribution coefficient of a substance.
To avoid the side effect of molecular UV blockers, the approach of using particulate UV blockers has been followed. An example is the widely used inorganic titanium dioxide (B. L. Diffey, P. M. Farr, Sunscreen protection against UVB, UVA and blue light; an in vivo and in vitro comparison, British Journal of Dermatology 124, 1991, 258-263). The basic idea was that the particles, by virtue of their size, do not diffuse into the skin and thus should not cause any side-effects. After sunbathing, the particles should be washed off the skin by normal body cleaning (e.g. shower).
Particulate UV blockers such as micropigments (e.g. titanium dioxide) have an immediately, conspicuous cosmetic disadvantage in preparations with a high light-protection factor. With the necessary large amount of pigment, a whitening effect occurs (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843). Very small titanium dioxide particles have proven to be particularly effective (B. L. Diffey, P. M. Farr, Sunscreen protection against UVB, UVA and blue light; an in vivo and in vitro comparison, British Journal of Dermatology 124, 1991, 258-263), so that they have accordingly been used at concentrations of up to 25% in cosmetics. However, interactions and side-effects with the skin have also bee n found with titanium dioxide particles (R. G. van der Molen et al, Efficacy of micronized titanium dioxide-containing compounds in protection against UVB-induced immunosuppression in humans in vivo, Journal of Photochemistry and Photobiology 44, 2, 1998, 143-150), and it can no longer be ruled out that titanium dioxide penetrates the skin (R. G. van der Molen, Tape stripping of human stratum corneum yields cell layers that originate from various depths because of furrows in the skin, Archives of Dermatological Research, 289, 9, 1997, 514-518). Thus it has been shown for example, that titanium dioxide can photocatalyze the formation of free radicals (W. G. Wamer, Oxidative damage to nucleic acids photosensitized by titanium dioxide, Free Radical Biology and medicine, 23, 6, 1997, 851-858), which is to be viewed critically both in the skin and on the skin and also during storage.
In summary it can thus be established that, in view of the more intensive radiation load, with a simultaneous increase in use, a need exists both for more efficient and toxicologically better compatible sunscreens, especially also for highly sensitive areas of the skin.
The object of the invention is to provide a better compatible agent for protection against harmful UV radiation which avoids the disadvantages described above and, in particular, greatly minimizes or avoids the redistribution of UV blockers from the dispersion phase (e.g. oil drops of a lotion) into the outer (dispersed) phase.
According to the invention, to achieve the object, the liquid lipids customarily used until now, from which molecules can easily diffuse, have been replaced by solid lipid and/or polymer in the form of solid, polymorphic, crystalline or partly crystalline lipid- and/or polymer particles of a size below 100 xcexcm (average size of the main population), which are characterized in that during the heating-up phase in thermal calorimetry (DSC Differential Scanning Calorimetry) above 20xc2x0 C. an endothermic peak is to be observed. Depending on requirements, UV blockers are incorporated into the solid lipid- and/or polymer particles. Sunscreens produced in this way are no longer emulsions, but technically constitute a suspension.
The expression xe2x80x9cpolymorphicxe2x80x9d refers to the property of molecules of being able to exist in different modifications. The polymorphic forms can be crystalline (fully crystalline) (e.g. xcex2-, xcex2i-modifications) or liquid-crystalline (e.g. xcex1-modification). When there are several different modifications (crystalline and liquid-crystalline), a partially crystalline form of the particles according to the invention can therefore also result. If only modifications with crystalline structure are present, the particles are also crystalline. If both regions with modifications with a crystalline structure and regions with a liquid-crystalline structure are present in the particles according to the invention, the particles are partially crystalline overall.
The stated particle sizes are the average of the main population. With small particles, it is the average diameters measured by photon correlation spectroscopy (PCS, measurement range 3 nm to 3 xcexcm) or laser diffractometry (LD). In the case of particles of  greater than 3 xcexcm, it is average diameters measured by laser diffractometry. Unless specified otherwise, it is the 50% LD diameter.
In the following, for the sake of simplicity, the invention is describe with reference to versions (a) which include lipids According to the invention, however, also included are versions (b) which include polymers, or versions (c) which contain lipids and polymers. Therefore, the explanations also apply to these alternative versions.
In ascertaining the UV-blocking action, it was surprisingly found that, compared with emulsions, the lipid particles already have a blocking action against UV radiation even without incorporated molecular UV blocker (Examples 1-3). This thus even opens up the possibility of dispensing with toxicologically unfavourable molecular UV blockers.
The UV-blocking action of the solid lipid particles decreases as the concentration increases, so that the desired light-protection factor can be set via the particle concentration (Example 4).
The UV-blocking action is also a function of particle size. Lipid nanoparticles, with identical lipid concentration in the suspension, were more effective than microparticles measuring 4.6 xcexcm (Example 5). This was confirmed by tests on polymer particles of varying size. Particles in the range of approx. 500 nm to 1000 nm showed the strongest UV-blocking action; very small nanoparticles (60 nm) and larger microparticles were leas effective (Example 7).
The data show that, in principle, polymer particles can be used as UV blockers, analogously to lipid microparticles. However, a disadvantage here is that inexpensive polymers such as polystyrene, poly(meth)acrylates, polycarbonates, polyamides or polyurethanes are not, or only slowly, degradable, and would heavily pollute the environment if used on a large scale in sunscreens. Biologically degradable polymers such as polyhydroxybutyric acid or polyhydroxyvaleric acid or polylactides are however, comparatively more expensive, which possibly limits their use in relatively low-priced sunscreens.
Polymer particles with a UV-blocking action can be prepared from various, chemically very different polymers. However, generally suitable as polymers are polymers which are solid at room temperature (20xc2x0 C.) such as polystyrene, polyacrylates, polymethacrylates, polycarbonates, polyamides, polyurethanes, polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), celluloses und cellulose derivatives, in particular cellulose hydrates, polylactides (PLAs), polyglycolide (PPGAs) and their copolymers (PLAs/GAs) individually or in a mixture. Mixtures of lipids and polymers can also be used.
However, lipid microparticles are ecologically most advantageous, especially if they are manufactured from renewable raw materials (e.g. vegetable lipids); at the same time, they are the most cost-favourable in economic terms.
The lipid particle suspension can be applied directly to the skin; if desired, a gelation agent can be added to increase viscosity. Alternatively, the particles can also be incorporated into lotions and creams. They are physically stable in them and do not dissolve in the oil phase (Example 6).
After being spread on a surface, the lipid particles form uniform films, a requirement for an effective UV-blocking action (Example 8). Perforated, porous films did not result, as feared, but instead the formation of a sealed film (Example 18). This lipid film strengthens the natural skin barrier, especially if a damaged natural lipid film is already present on the stratum corneum.
UV blockers can also be incorporated into the lipid particles in order to additionally increase the UV-blocking action (Examples 11 and 12). Surprisingly, it was discovered that the effect of lipid particles and UV blockers can be not only additive, but also synergistic (Example 17).
As exposure to the sun can mean stress for the skin, it can be advisable to incorporate skin-care substances, such as retinol palmitate or antioxidants such as tocopherol, into the lipid particles. Both active substance groups can also be processed simultaneously.
The lipid particles according to the invention can also be used to minimize the interaction of inorganic or organic pigments with the skin. Analogously to the molecular UV blockers, the pigments (pigmentary or particulate UV blockers) are enclosed in the solid lipid matrix. The enclosure can also take place without problems in lipid particles in the lower nanometer range (e.g. 200 nm particles), as many pigments are very small (approx. 10-40 nm with magnesium layer silicates such as Aerosil, approx. 15-20 nm in the case of titanium dioxide) (Examples 15 and 16).
It is also possible to incorporate a combination of molecular UV blockers and particulate UV blockers (pigments) as well as simultaneously add skin-care active substances as well as antioxidants, either into the solid lipid matrix or to the outer phase of the lipid particle dispersion.
The lipid particle dispersions according to the invention can also be manufactured free of emulsifiers, which is important for the avoidance of Mallorca acne. Mallorca acne is not triggered by UV-A radiation alone, but by its interaction with emulsifiers in cosmetics (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843).
Additionally, there are possible applications on the scalp and hair (e.g. to avoid sunburn with thin hair, avoidance of bleaching effects on hair). Particularly to increase the adhesion to negatively charged hair, the lipid particles can be produced with a positive charge by using suitable surfactants.
To increase acceptance of the UV absorption agent, natural, synthetic or semi-synthetic fragrances can be incorporated into the lipid particles, e.g. perfumes, ethereal oils or pheromones.
Examples of perfumes are Allure, Coco, Egoiste, Chanel No. 5, 19, 22 from Chanel, Miss Dior, Dune, Diorissime or Fahrenheit from Dior, Roma, Laura, Venezia from Laura Biagotti, L""air du temps from Nina Ricci, Chalimar from Guerlain, Tresor from Lancome, Gio from Armani, Escape, Obsession, CK One, CK be, Eternity from Calvin Klein, Berlin, Joop, Rococo, All about Eve, What about Adam, Nightflight from Joop, KL, Lagerfeld, Jako from Karl Lagerfeld, Extreme from Bulgari.
Examples of ethereal oils are lemon oil, rose oil, lavender oil, bergamot oil, balm mint oil, clove oil, cinnamon oil, orange oil, jasmine oil, rosemary oil, aniseed oil, peppermint oil, sandal wood oil, ylang-ylang oil or their isolated ingredients such as e.g. 1,8-cineole, menthol, terpinol hydrate, limonene, xcex1-pinene, eugenol.
Examples of pheromones are in particular, human pheromones such as androstenone or androstenol.
The scents can be incorporated into the lipid particles alone or in combination with, for instance, UV blockers such as e.g. particulate or molecular UV blockers.
To use the agent for UV absorption in areas plagued by insects, (e.g. mosquitoes on Indian beaches), repellents can be incorporated into the lipid particles. Examples of repellents are natural repellents such as citrus oils, eucalyptus oil und camphor or synthetic repellents such as N,N-diethyl-toluamide (DEET), dibutyl phthalate, dimethyl phthalate, 2-ethyl-1,3-hexanediol.
The repellents can be incorporated into the lipid particles alone or in combination with scents and/or UV blockers such as e.g. particulate or molecular UV blockers.
The invention is described in more detail in the following with the help of the attached FIGS. 1 to 18 and examples.